bay-12-9566 and deoxypyridinoline

Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and have been implicated in breast, ovarian, colorectal, and lung cancer growth. We undertook a phase I study of BAY 12-9566, an inhibitor of MMP-2, MMP-9, and MMP-3, in patients with solid tumors to determine its safety, pharmacokinetics, and effects on potential surrogate markers of biologic activity.. BAY 12-9566 was orally administered daily at four dose levels; 400 mg daily, 400 mg b.i.d., 400 mg t.i.d., and 800 mg b.i.d. Drug disposition was determined on days 1 and 29 with weekly trough levels measured during the first four weeks. Plasma vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and urinary pyridinoline and deoxypyridinoline crosslinks were determined at baseline, once weekly for four weeks, and then every four weeks.. Thirteen patients were entered on trial. BAY 12-9566 was well tolerated, with only one grade 3 headache, one grade 3 anemia, one grade 3 thrombocytopenia, and no musculoskeletal effects. The median treatment duration was 57 days (range 7-560). Mean trough levels of BAY 12-9566 on day 28 ranged from 80.5 to 108.6 mg/l. Plasma trough levels were 1500-42,000-fold above the Ki's for MMP-2, MMP-3, and MMP-9 at the 800 mg p.o. b.i.d. dose level. There was no significant change in VEGF, bFGF, pyridinoline, and deoxypyridinoline crosslinks with BAY 12-9566 administration.. The recommended dose for further testing is 800 mg p.o. b.i.d.

Topics: Adult; Amino Acids; Antineoplastic Agents; Biphenyl Compounds; Dose-Response Relationship, Drug; Endothelial Growth Factors; Enzyme Inhibitors; Female; Fibroblast Growth Factor 2; Humans; Lymphokines; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Maximum Tolerated Dose; Middle Aged; Neoplasms; Organic Chemicals; Phenylbutyrates; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

BAY 12-9566 (4-[4-(chlorophenyl)phenyl]-4-oxo-2S-(phenylthiomethyl) butanoic acid) is a newly developed, synthetic matrix metalloproteinase (MMP) inhibitor (MMPI) that selectively inhibits MMP-2, MMP-3 and MMP-9 isozymes. We study the effect of BAY 12-9566 on inflammation and cartilage destruction in adjuvant-induced arthritis (AA) in rats. Rats were injected with adjuvant and treated for 21 days with vehicle, Indomethacin or BAY 12-9566. AA was assessed: by measuring arthritic index, paw volume, urinary pyridinoline (Pyr) and deoxypyridinoline (Dpyr); by examining joint inflammation; and by microscopic morphometry of articular cartilages. Oral treatment of rats for 22 days with 50 mg kg(-1) body weight/d BAY 12-9566 showed decreased AA as determined by improvement in body weight gain (P<0.01), arthritic index (P<0.05) and swelling of paws contralateral to the adjuvant injection site (P<0.05). Neutrophil infiltration and collagen degradation were also significantly lower (P<0.01) in this treatment group. Cartilage destruction was successfully suppressed (P<0.01) in rats treated with either 50 mg kg(-1) body weight/d BAY 12-9566 or 1 mg kg(-1) body weight/d Indomethacin. These results indicate that BAY 12-9566 successfully suppressed inflammation and cartilage destruction in rats with AA. Moreover, these results also suggested that MMP-2, MMP-3 and MMP-9 are involved in arthritic diseases such as rheumatoid arthritis.

Topics: Amino Acids; Animals; Antineoplastic Agents; Arthritis, Experimental; Biphenyl Compounds; Body Weight; Edema; Hindlimb; Indomethacin; Inflammation; Male; Matrix Metalloproteinase Inhibitors; Organic Chemicals; Phenylbutyrates; Rats; Rats, Sprague-Dawley; Weight Gain